# the mTOR translational control pathway in tamoxifen resistant ER+ breast cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $440,359

## Abstract

Project Summary. Estrogen receptor positive (ER+) breast cancers comprise the majority (~70-80%) of
breast cancers, the majority of late recurrences emanating from indolent or dormant breast cancer, and the
majority of breast cancer deaths resulting from metastatic disease. Anti-endocrine therapy with tamoxifen
remains the cornerstone of adjuvant therapy for ER+ breast cancers, particularly in premenopausal women,
but also following treatment with aromatase inhibitors in the post-menopausal setting. Nevertheless, many
women do not respond to tamoxifen in initial therapy, and of those that do, one third will relapse with resistant
and metastatic disease within 15 years. Endocrine resistant ER+ breast cancers therefore remain one of the
major causes of breast cancer metastasis and mortality. In fact, initial or acquired resistance to tamoxifen is
involved in more than half of all ER+ breast cancer deaths. Reversing resistance to tamoxifen therapy is a
crucial overarching breast cancer challenge.
We provide preclinical research demonstrating the discovery of a crucial axis that provides tamoxifen
resistance to ER+ breast cancer cells mediated by the epidermal growth factor receptor (EGFR)/estrogen
receptor α (ERα) pathways, and their impact on selective mRNA translation through the kinase mTOR.
Moreover, we demonstrate that there are several experimental drugs developed for other indications that can
be repurposed to target this axis for the treatment of tamoxifen resistant ER+ breast cancers. Tamoxifen is an
estrogen receptor antagonizing small molecule used for treatment for ER+ breast cancer worldwide.
Resistance is well established to commonly involve overexpression of EGFRs on breast cancer cells, and
hyper-activation or increased signaling of the MAPK-ERK and PI3K-Akt-mTOR pathways. We have now
identified two novel hyperactivated mediators of resistance to tamoxifen therapy that lie at the intersection of
these key pathways, and we show their importance in resistance. The two effectors of tamoxifen resistance are
the inhibitor of translation initiation factor eIF4E, known as 4E-BP1, and the phosphorylation of eIF4E by hyper-
activation of its ERK associated kinase, MNK1. Both are therapeutic targets for existing experimental drugs
developed for other purposes with good toxicity profiles. eIF4E comprises the basic translation component for
loading ribosomes onto mRNAs. Many studies by my group and others have shown that increased
phosphorylation of eIF4E is controlled by the ERK-MNK1 pathway, and its increased abundance is controlled
by the mTOR/4E-BP1 pathway, which selectively upregulates translation of specific mRNAs required for
survival, proliferation and metastasis of breast cancer cells.

## Key facts

- **NIH application ID:** 10166782
- **Project number:** 5R01CA207893-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Robert Jay Schneider
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,359
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166782

## Citation

> US National Institutes of Health, RePORTER application 10166782, the mTOR translational control pathway in tamoxifen resistant ER+ breast cancer (5R01CA207893-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10166782. Licensed CC0.

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